Pembrolizumab, an anti-programmed death 1 monoclonal antibody, underwent a rapid clinical development program for the treatment of patients with malignancies in parallel to the development of a companion diagnostic for detecting programmed death ligand 1 (PD-L1) expression, which was considered to be a likely biomarker for response and cancer outcome. When investigating outcomes in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, PD-L1 tumor proportion score (TPS) was initially identified as a marker of clinical efficacy, with a cutoff of ≥ 50%. This threshold was later reduced to TPS ≥ 1%, which demonstrated that pembrolizumab offered a clinical benefit in a broader population of patients with PD-L1-expressing tumors. As new evidence emerged, it also became clear that immune cell PD-L1 expression has an important role in predicting tumor response in patients treated with pembrolizumab; the combined positive score (CPS), which accounts for both tumor and immune cell PD-L1 expression, was then applied in clinical studies for indications outside of NSCLC. This review summarizes the outcomes of landmark studies in the KEYNOTE clinical development program that investigated the efficacy of pembrolizumab in patients with a variety of malignancies, the relative outcomes when patients were stratified by PD-L1 status, and how these observations have influenced the approved indications for pembrolizumab.